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Thursday, June 30, 2016

VistaGen's AV-101 Is A Potential Blockbuster For MDD

Major depression is a significant healthcare burden in the developed world. Patients with major depressive disorder (MDD) experience poor quality of life and often battle debilitating symptoms, including depressed mood, apathy, insomnia, fatigue, dementia, agitation, and suicidal ideation. Despite the availability of dozens of blockbuster pharmaceutical products, MDD remains a challenging medical condition to treat. Treatment-resistant MDD, a condition that affects 10-30% of all MDD patients (1), is a key focus of VistaGen Therapeutics, Inc. (NASDAQ: VTGN).

VistaGen is developing AV-101 (4-chlorokynurenine or 4-CL-KYN), an oral prodrug of 7-chlorokynurenic acid (7-Cl-KYNA) that has demonstrated impressive antidepressant effects and safety in preclinical and Phase 1 studies. AV-101 is a glycine B (GlyB) receptor antagonist that negatively modulates the N-Methyl-D-aspartic acid (NMDA) receptor and may induce synaptogenesis. It's a fundamentally different pathway from standard antidepressants and similar to the glutamatergic AMPA-dependent pathway of ketamine; but, without the potential negative side effects of NMDA ion channel blocking.

AV-101 is currently being studied in an ongoing Phase 2a clinical trial fully sponsored by the U.S. National Institute of Mental Health (NIMH), the purpose of which is to assess the antidepressant effects and safety of the drug candidate in patients with treatment-resistant MDD. The twenty-five patient, placebo-controlled study is taking place at the NIH Clinical Center in Bethesda, MD, under the principal investigation of Carlos A. Zarate, MD. Dr. Zarate has authored over 100 papers, including paradigm-shifting work with ketamine in the treatment of bipolar depression and treatment-resistant MDD, and is one of the nation's foremost experts in MDD.

In this article, I look at the depression market, what recent understanding on the mechanism for ketamine and NMDA receptor antagonism means for investors, and how VistaGen's AV-101 could become a significant player in this market in the next twelve months.

Treating Major Depression - A Daunting Challenging

Depression is one of the most common mental disorders in the U.S. According to the CDC's National Center for Health Statistics, 7.6% of the U.S. population over the age of 12 years suffer from depression (2). This equates to approximately 21 million individuals, about one-third of which are characterized as having major depressive disorder (3). Depression results in roughly 8.0 million ambulatory care visits to a physician's office, hospital, or emergency department each year and accounts for just over 8% of all disability claims in the U.S. (4).

Major depression is typically treated with a combination of pharmacotherapy and psychotherapy. Antidepressant medications were the third most common prescription drugs taken by Americans of all ages between 2005 and 2008 (5). The most widely used first-line agents are selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, citalopram, escitalopram, paroxetine, and sertraline. These drugs work by increasing the level of serotonin and, to a lesser extent, dopamine in the brain.

Other typical agents for the treatment of depression include serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, and duloxetine, tricyclic antidepressants (TCAs) such as amitriptyline, clomipramine, and doxepin, and monoamine oxidase inhibitors (MAOIs) such as isocarboxazid, phenelzine, selegiline, and tranylcypromine. Similar to the SSRIs, these drugs work to increase monoaminergic and GABAergic transmission in the brain (6). However, all the agents mentioned above carry an FDA "Black Box" warning for increased risk of suicide associated with these drugs (7).

Despite the presence of some blockbuster drugs (shown above), prolonged response rates to first- and second-generation antidepressants are only around 50% (8). That means half the patients taking these drugs fail and seek alternative treatments. Many will switch around among the various available antidepressants; although, results from the 4,000-patient NIMH-sponsored STAR*D trial show this strategy offers diminishing returns (9).

A 2007 report by the Agency for Healthcare Research and Quality (AHRQ) compared the effectiveness of second-generation antidepressants by reviewing available literature and reported data from 187 randomized and/or placebo-controlled clinical trials. For patients diagnosed with MDD, 38% of patients did not respond at all to treatment and only 46% achieved remission (10). Issues such as: not staying the drug long enough, skipping doses, unpleasant side effects, drug-drug interactions, slow onset of action, alcohol or drug abuse, and improper mechanism are believed to be the major contributing factors to the poor response rate and high incidence of treatment-resistance among MDD patients (11).

For example, results from the STAR*D trial conducted by the NIMH found that the average time to remission was 5.4 to 7.4 weeks. In other words, MDD patients did not begin to see a clinical benefit until over a month after initiation of treatment. This lag time is far too long between initial symptoms such as suicide ideation and clinical efficacy and a major drawback to currently available MDD treatments (12). The initial treatment period for antidepressants is when suicide risk is the highest and slow-acting drugs like SSRIs and SNRIs can increase the risk of suicide upon initiation of therapy (13). Conversely, ketamine, an NMDA-receptor antagonist, has been shown to provide rapid resolution of suicidal ideation after only a single dose (14).

The NMDA-Receptor - A Major Mediator of Psychiatric Pathology

Recent compelling evidence has suggested that the glutamate system is a primary mediator of psychiatric pathology and also a target for rapid-acting antidepressants (15). The NMDA receptor is a glutamate-gated ion channel widely expressed in the central nervous system that plays a key role in excitatory synaptic transmission (16). Abnormalities of glutamate and NMDA receptors contribute an imbalance in glutamatergic neurotransmission, which may contribute to increased levels of NMDA agonism, thereby enhancing excitatory activity in most brain circuits involved in patients with major depression (17). Rapid responses in subjects with treatment-resistant depression suggest a mechanism that results in fast changes in synaptic function and plasticity (18).

- Ketamine

While its mechanism of action remains unclear, ketamine, which has a moderately high binding affinity for and can block the activity of, the NMDA receptor, is making headlines as a breakthrough in the treatment of depression. In May 2016, a team of researchers out of the U.S. NIMH and the University of Maryland announced they may have discovered a potential breakthrough using a metabolite, or chemical byproduct, of racemic (R,S)-ketamine to reverse depression-like behavior.

The findings, published in Nature (19), show that a single administration of a metabolite of R-ketamine, called (2R, 6R)-hydroxynorketamine (HNK), resulted in rapid antidepressant-like effects in mice without ketamine-related side effects, such as anesthesia, or dissociative or addictive behavior. (2R, 6R)-HNK, through unknown intermediates, increases the levels of another neuronal receptor protein, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). The data may implicate a novel mechanism underlying the antidepressant properties of racemic (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants (20).

Over the past decade, ketamine’s enormous potential in the treatment of mental health issues has become a focus for researchers and psychiatrists trying to come up with a solution to severe depression where currently available medications have failed (21). Since 2006, dozens of studies have reported that ketamine can also reverse the kind of severe depression that traditional antidepressants often don’t resolve. The momentum behind the drug has now reached the American Psychiatric Association, which, according to members of a ketamine task force, seems headed toward a tacit endorsement of the drug for treatment-resistant depression (22).

The mechanisms of action for ketamine and other NMDA-receptor antagonists is one of enhancing synaptic function through a shift in activity to the AMPA receptor precipitated by non-competitive inhibition of the NMDA receptor. Administration of ketamine increases extracellular levels of glutamate in the prefrontal cortex. The resulting burst of glutamate caused by ketamine then leads to activation of the signaling machinery (stimulation of BDNF-mTORC1 cascade) that stimulates synapse formation (23). Pre-administration of rapamycin, a selective mTORC1 inhibitor, blocks these effects.

The mechanism of action is one that could reverse mTOR blockage and synaptic deficits caused by long-term exposure to stress or chronic depression (24), sparking synaptogenesis and reversing depression in patients that have failed existing medications such as SSRIs or SSNIs.

Investigators at the U.S. NIMH seem rather excited about the potential of this new mechanism of action for the treatment of depression. As noted above, scientists have long assumed that NMDA-receptor targeting has antidepressant-like effects, but the chronic antagonism of the receptor by ketamine is not tolerable. Ketamine, colloquially known as "Special K", is addictive and has a high potential for abuse or misuse (25). The NIMH study is only testing a single dose of ketamine (26), so while the results to date have been very encouraging, researchers are a long way away from a solution (side note: the principal investigator on that ketamine study is Dr. Zarate, the same principal investigator in VistaGen's ongoing Phase 2a study).

- Esketamine (Johnson & Johnson)

Johnson & Johnson (NYSE: JNJ) is currently conducting a Phase 3 clinical trial with esketamine (27), an intranasal formulation of the S(+) enantiomer of ketamine for the treatment of MDD. J&J believes that esketamine has the rapid antidepressant effects of racemic (R,S)-ketamine without the nasty side effects. It is similar to the strategy that Dr. Zarate and colleagues at the NIMH took with the R-ketamine metabolite, (2R, 6R)-hydroxynorketamine (HNK), for their recent paper in Nature (28).

- d-methadone (Relmada Therapeutics)

Relmada Therapeutics (OTC: RLMD) is currently developing dextro-methadone, the d(+) enantiomer of racemic (d,l)-methadone. Methadone is a synthetic opioid analgesic used as an alternative to morphine and as a replacement for heroin in medically-supported maintenance or detoxification programs (29). Recent findings show that the analgesic effect of the molecule (µ-opioid receptor activity) stems from the levo-enantiomer, whereas the dextro-enantiomer has NMDA-receptor activity with low potential for addictiveness or psychological side effects (30).

In May 2016, Relmada released results from a preclinical study showing d-methadone has antidepressant-like effects similar to what has been seen recently with ketamine (31). Specifically, the company studied d-methadone in a well-validated rodent behavioral despair test, also known as the rat forced swim test (32). Results show that a single administration of d-methadone decreased the immobility of the rats compared to the vehicle, suggesting antidepressant-like activity larger than the effects of ketamine, also tested in the study.

- CERC-301 (Cerecor Inc.)

Cerecor Inc. (NASDAQ: CERC) is developing CERC-301, a selective NR2B antagonist of the NMDA receptor subunit. NMDA receptor channels are heteromers composed of the key receptor subunit, NR1, and one or more of the six subunits, NR2A, NR2B, NR2C, NR2C, NR3A, and NR3B. NR2B is the glutamate binding side of the NMDA receptor and important in synaptic signaling events and protein-protein interactions. The NR2B subunit is involved in modulating functions such as learning, memory processing, pain perception, and feeding behaviors, as well as many human disorders (33).

Merck initially developed CERC-301 (then called MK-0657) for the treatment of Parkinson’s disease, but the trial ultimately failed, and Merck discontinued development. At the time of the Parkinson's trial failure, a Phase 2 study in MDD was enrolling patients. Truncated results from the study show no significant improvement in patients receiving MK-0657 compared to placebo as assessed by the primary outcome measure (MADRS). However, MK-0657 was shown to improve depressive symptoms when assessed by the Hamilton Depression Rating Scale (HDRS) and the Beck Depression Inventory (BDI) (34). Cerecor has since acquired the asset from Merck and is pursuing development of CERC-301 as an adjunctive medication in patients with severe MDD who are not responding to current antidepressants.

- rapastinel (Allergan plc)

In July 2015, Allergan plc. (NYSE: AGN) acquired privately-held Naurex for $571.7 million in cash upfront, plus up to an additional $1.15 billion in future potential milestone payments (35). Allergan is developing rapastinel (GLYX-13), a NMDA receptor modulator with GlyB site partial agonist properties. Preclinical and early-stage clinical data points to rapid and long-lasting antidepressant activity, along with potential cognitive improvements in patients with post-traumatic stress disorder (PTSD) (36). In January 2016, the U.S. FDA awarded Breakthrough Therapy Designation to rapastinel as an adjunctive treatment for MDD (37).

Rapastinel's rapid-acting antidepressant properties appear to be mediated by its ability to activate NMDA receptors leading to enhancement in synaptic plasticity processes associated with learning and memory. Alterations in dendritic spine morphologies associated with the maintenance of long-term changes in synaptic plasticity have been demonstrated in rats following single dose injections of rapastinel (38). These data suggest that rapastinel produces its long-lasting antidepressant effects via triggering NMDA receptor-dependent processes leading to hippocampal long-term potentiation (39).

VistaGen's AV-101 - A New Approach That Has Piqued KOL Interest

VistaGen Therapeutics is developing AV-101, an orally available prodrug candidate rapidly converted in vivo into its active metabolite, 7-chlorokynurenic acid (7-Cl-KYNA). 7-Cl-KYNA is a full antagonist of the GluN1 subunit with a similar mechanism to rapastinel (note: rapastinel is a partial agonist). Naurex own preclinical data shows that that AV-101 is a more potent GlyB site modulator (40). Additionally, and significantly, AV-101 is orally available whereas rapastinel, like ketamine, is an intravenous injection (41).

The cartoon below is a representation of the NMDA receptor pharmacology showing the different targets for ketamine, d-methadone, CERC-301, rapastinel, and AV-101.

Preclinical: Preclinical data published in the Journal of Pharmacology & Experimental Therapeutics demonstrates that AV-101 has rapid, dose-dependent and persistent antidepressant-like effects assessed by multiple validated animal models following a single treatment, similar to ketamine and distinct from fluoxetine, but without the negative behavioral effects of potential abuse, psychotomimetic effects, locomotor sensitization, or other stereotypic behaviors common to hallucinogenic drugs (42).

Phase 1: Two Phase 1 studies have been completed to date with AV-101. A 36-subject, randomized, double-blind, placebo-controlled Phase 1a study assessed tolerability in six single sequential doses of the drug. A 48-subject, randomized, double-blind, placebo-controlled Phase 1b study assessed multiple ascending-dose of the drug (360, 1080, 1440 mg). Data from both studies show subjects experienced positive feelings of well-being compared to none on placebo, without any ketamine-like negative side effects. Pharmacokinetic data showed dose proportionality with Tmax of 1-2 hours and a half-life of 2-3 hours. These data compare favorably to the half-life of only 5-8 minutes for rapastinel (43).

Phase 2a: AV-101 is currently being studied in an NIMH-sponsored Phase 2a clinical trial (NCT02484456) taking place at the NIH Clinical Center in Bethesda, MD, under the principal investigation of Carlos A. Zarate, MD. As noted above, Dr. Zarate is one of the nation's foremost experts in the field of depression and has authored over 100 papers on the subject, including paradigm-shifting work with ketamine recently published last month in Nature (44). Target enrollment for this study is 24 to 28 adult subjects with treatment-resistant MDD. Data are expected during the first half of 2017.

Phase 2b: VistaGen is currently planning a company-sponsored Phase 2b study with AV-101 separate from the NIMH-sponsored Phase 2a study noted above. The Phase 2b study will be a randomized, double-blind, placebo-controlled study targeting enrollment of 200-300 patients with inadequate response to standard antidepressants. Oral doses of AV-101 will be studied as an adjunctive treatment to background antidepressants in a sequential parallel comparison design (SPCD). SPCD (shown below) was established by the Massachusetts General Hospital Psychiatry Academy to mitigate placebo-response and assess the true efficacy of the drug over a two-stage format.

The primary endpoint is efficacy as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS), with secondary endpoints in additional widely-accepted measures of mood, depression, and cognition, including HAM-6, CGI-S, CGI-I, and SDQ. Maurizio Fava, M.D. of the Massachusetts General Hospital and Professor of Psychiatry at Harvard Medical School, is the principal investigator of this study. Dr. Fava was the lead investigator on the NIMH-sponsored STAR*D trial discussed above. Between Dr. Zarate and Dr. Fava, VistaGen has some pretty impressive individuals running its clinical programs with AV-101. The company's clinical and regulatory advisors are equally impressive thought-leaders in the area of psychiatry (45).

VistaGen has selected PPD to execute the Phase 2b study. PPD is a leading global contract research organization (CRO) that provides comprehensive, integrated drug development, laboratory, and lifecycle management services to biopharmaceutical companies. PPD has extensive expertise in mood-related clinical studies and has built significant infrastructure around Harvard’s SPCD protocol design. The Massachusetts General Hospital (MGH) Clinical Trials Network and Institute (CTNI) is an academic CRO within the psychiatry department at MGH. PPD and CTNI will work together in a unique partnership to ensure SPCD trial methodology and efficient trial operations. A total of 20 to 25 sites around the U.S. are expected to enroll patients.

AV-101 Market Opportunity

According to the CDC's National Center for Health Statistics, 7.6% of the U.S. population over the age of 12 years suffer from depression (46). Based on 2015 Census data, this equates to approximately 21 million individuals. Data from the U.S. NIMH pegs the number slightly lower at 6.7% of all U.S. adults, equating to 16 million individuals (47). Major depressive disorder (MDD) affects about one-third of the total population diagnosed as with any depressive disorder (48).

According to NIMH research, about half of U.S. patients with MDD receive treatment (49). Results of the 4,000-patient STAR*D trial showed remission rates of 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67% (50). The 33% that fails to show response are classified as having treatment-resistant depression. The numbers work out to a target of around one million patients.

This is the target market for drugs such as esketamine, rapastinel, dextro-methadone, CERC-301, and AV-101. I think esketamine is the lead horse in this race due to the stage of development (in Phase 3), brand recognition (ketamine use is wide-spread), and the capabilities of the company developing the drug (J&J). One can assume that if first to market, esketamine will capture 50% of the initial target population; however, potential scheduling issues and an unclear safety profile for esketamine might limit upside and allow competitors to gain sizable share once approved.

After J&J, the race is relatively wide-open. Investors can argue that rapastinel is likely the next horse to beat given its position in development (entering Phase 3) and the capabilities of Allergan, with small-caps such as Relmada, Cerecor, and VistaGen battling it out for third place. But AV-101 has several advantages over rapastinel that lead me to believe VistaGen will give Allergan a good run for its money for second place. Mainly, greater potency (full agonist of the GlyB binding site versus only partial agonism of rapastinel) and oral dosing (rapastinel is IV). I plan to cover this in greater detail in my next article.

Nevertheless, 20% market share equates to around 200,000 patients on AV-101 at peak. If we assume pricing comparable to branded antidepressants / branded atypical antipsychotics, which cost around $25 per day, with 90% compliance, a full year worth of treatment will cost around $8,213 in the U.S. This puts peak sales of AV-101 at $1.65 billion. Outside the U.S., the opportunity is likely another $825 million, putting peak global sales of AV-101 for treatment-resistant MDD at roughly $2.45 billion.


VistaGen Therapeutics currently trades with a market capitalization of only $28 million. The stock seems vastly undervalued at today's level. Keep in mind, Allergan paid $571.7 million in cash upfront to acquire Naurex’s rapastinel and an earlier stage drug candidate, NRX-1074, less than a year ago, and that value does not include the greater than $1 billion in backend potential milestones. Importantly, Naurex’s own preclinical data show that rapastinel effects are completely blocked by 7-Cl-KYNA, the active metabolite of AV-101 (51) - showing AV-101 has greater potency than rapastinel - and that AV-101 has a longer half-life and wider therapeutic range (52). Oral dosing is also a significant advantage for AV-101 over rapastinel.

Given these facts, one could argue that VistaGen Therapeutics will be worth at least $571.7 million if the planned Phase 2b trial with AV-101 is successful. Based on data compiled by BIO and Biomedtracker in June 2016, the average success rate for a Phase 2 clinical trial in neurology is 30% (53). That would place the current value for VistaGen, set by Allergan's acquisition of Naurex, at $171 million, or around $21 per share (basic) as of today. A $21 target on a $3.50 stock may seem aggressive, but keep in mind that as of his last report (Feb. 2016), Chardan Capital analyst, Gbola Amusa, MD, CFA, had a $50 price target on VistaGen!

Above I outlined why I believe that AV-101 has potential peak sales in the U.S. of $1.65 billion. I think peak sales outside the U.S. are easily another $825 million, putting total global peak sales at roughly $2.45 billion for treatment-resistant MDD. If successful in this indication, it is logical to assume that VistaGen will test AV-101 as a first-line monotherapy, which could potentially double the peak sales opportunity. The Phase 2b trial should report top-line results during the first half of 2018. The ongoing Phase 2a study being conducted by Dr. Zarate at the NIMH should report top-line data in the second quarter of 2017. Assuming positive data from these two Phase 2 studies, I think AV-101 will be in Phase 3 in 2019, putting VistaGen in a position to file the NDA in 2022. Peak sales of AV-101 are likely several years thereafter.

If we assume peak sales for AV-101 at $2.45 billion roughly ten years from today and apply an industry-average 6x EV/Revenue multiple (source: Morgan Stanley, 54), VistaGen would be worth $14.8 billion in value in 2028. Discounting this back to present day at 22.5% and applying a 15% success rate to commercialization for a Phase 2 neurology asset (source: BIO/Biomedtracker, 55), VistaGen is worth approximately $194 million, or around $24 per share (basic). This value is similar to the valuation of $171 million ($21 per share) estimated by the Allergan-Naurex transaction.



Depression is a debilitating disease that affects approximately 16 to 21 million Americans. Roughly one million of these individuals has major depression that is resistant to conventional antidepressants. Abnormalities of the NMDA receptor contribute to imbalances in glutamatergic neurotransmission that may lead to depressive pathology. Antagonism of the NMDA receptor by ketamine has been shown in both preclinical and clinical models to reverse depressive states rapidly and resolve suicidal ideation after only a single dose.

Several pharmaceutical companies are developing drugs that target the NMDA receptor, including behemoths Johnson & Johnson and Allergan. Micro-cap VistaGen Therapeutics is developing AV-101, an oral byproduct of 7-Cl-KYNA, a full antagonist of the NRI (GlyB) subunit of the NMDA receptor. Investigators at the NIMH are currently studying AV-101 in a Phase 2a clinical trial. The company plans to move AV-101 into a Phase 2b clinical trial in the next few months. I believe if successfully commercialized, AV-101 has peak sales of approximately $1.65 billion in the U.S. and $2.45 billion worldwide.

VistaGen recent secured $10 million in cash through a public offering in May 2016 (56). The company is now well-capitalized to advance AV-101 into late-stage clinical studies. There is minimal risk of dilution over the next several months. Valuation comparable analysis suggests the company is worth $171 million today. Traditional valuation methodology using industry average multiples and historical rates of success suggest a similar valuation for the company at around $194 million. This puts the stock fairly valued at a range between $21 and $24 per share (basic), resulting in over 500% upside from today.


This article was written by Jason Napodano, CFA of BioNap, Inc.
Please see additional information on our Disclaimer.


  1. From Vistagen's own website:

    Although the Phase 1 safety and pharmacokinetic studies were not designed to measure or evaluate the potential antidepressant effects of AV-101, approximately 9% (5/54) of the subjects receiving AV-101 and 0% of the 30 subjects receiving placebo reported “feelings of well-being” similar to the fast-acting antidepressant effects reported in the literature with ketamine.

    This is not exactly Earth-shattering efficacy. Additionally, it's not at all accurate to say that it's on par with ketamine. If you speak with the handful of doctors actively doing ketamine iv drips to treat atypical depression, you'll learn that most of them say it works on about 2/3 of their patients. Dr. Brooks in NYC and Dr. Levine at Princeton are two such reputable doctors who have been doing ketamine infusions for years.

    It would be great if AV-101 can replicate the rapid anti-depressant effects of ketamine, but frankly, it doesn't seem likely given the existing data. Esketamine has the best chance of all of the glutamatergic drugs being tested. Their trial is poorly designed though, so I won't be shocked if it doesn't get approved.

    1. Thanks for your comment!

      I wouldn't put any weight on P1 pk studies to get a sense of efficacy. I'd look at the AGN data with rapastinel for that, and likely believe the AV-101 is superior based on the pk data. As for esketamine, I'd be concerned about scheduling and potential ketamine-like side effects. I also like that AV-101 is oral, so you have the ability to dose like Abilify.

      Side note, what do you think of d-methadone for this indication?

  2. A very interesting article and meticulously researched. Since I don't have a medical background it was quite difficult to understand. Could you tell me how does AV-101 compare with Neuralstem's NSI 189?

    1. Very different mechanisms. AV-101 targets the NMDA receptor. NSI-189 creates neurogenesis in the hippocampus and may even reverse hippocampal atrophy. How NSI-189 works, no one has any idea. I'm not sure even CUR knows. The P1 data with NSI-189 were confusing and the market did not find them terribly impressive. Dr. Fava at Harvard was the PI of the program. It would be interesting to get his take on AV-101 vs. NSI-189 because he has moved his attention to AV-101 for Phase 2. I'm not sure what the status of NSI-189 is at this point. CUR is a company in trouble, so at this stage I would not bet anything on NSI-189. AV-101 is in Phase 2a and will start Phase 2b in the coming months. That's something you can hang your hat on.

    2. According to a May 12th press release Neuralstem has enrolled the first patient for its Phase 2 trial of NSI 189. I had no idea Dr.Fava was also running the AV 101 trial. Its not very clear ,however, how Neuralstem is going to fund the trial; as you say they look like a company in trouble. It would be very interesting to get Dr.Fava's view on AV 101 vs NSI 189 ,he was quite upbeat about the Phase 1 trial of NSI 189. How approachable is he?